Li Lianjie, Zhang Liang, Zhang Xiaoping, Yan Qin, Minamishima Yoji Andrew, Olumi Aria F, Mao Mao, Bartz Steven, Kaelin William G
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Mayer 457, Boston, MA 02115, USA.
Mol Cell Biol. 2007 Aug;27(15):5381-92. doi: 10.1128/MCB.00282-07. Epub 2007 May 25.
Clear cell carcinoma of the kidney is a major cause of mortality in patients with von Hippel-Lindau (VHL) disease, which is caused by germ line mutations that inactivate the VHL tumor suppressor gene. Biallelic VHL inactivation, due to mutations or hypermethylation, is also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for destruction under well-oxygenated conditions. All VHL mutations linked to classical VHL disease compromise this pVHL function although some missense mutations result in a low risk of kidney cancer (type 2A VHL disease) while others result in a high risk (type 2B VHL disease). We found that type 2A mutants were less defective than type 2B mutants when reintroduced into VHL-/- renal carcinoma cells with respect to HIF regulation. A stabilized version of HIF2alpha promoted tumor growth by VHL-/- cells engineered to produce type 2A mutants, while knock-down of HIF2alpha in cells producing type 2B mutants had the opposite effect. Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations.
肾透明细胞癌是冯·希佩尔-林道（VHL）病患者死亡的主要原因，该病由种系突变引起，这些突变使VHL肿瘤抑制基因失活。由于突变或高甲基化导致的双等位基因VHL失活在散发性肾透明细胞癌中也很常见。VHL基因产物pVHL是泛素连接酶复合物的一部分，该复合物在氧合良好的条件下靶向异二聚体转录因子缺氧诱导因子（HIF）的α亚基进行降解。所有与经典VHL病相关的VHL突变都会损害这种pVHL功能，尽管一些错义突变导致肾癌风险较低（2A型VHL病），而另一些则导致高风险（2B型VHL病）。我们发现，当重新引入VHL-/-肾癌细胞时，2A型突变体在HIF调节方面比2B型突变体缺陷更少。稳定化的HIF2α促进了经工程改造产生2A型突变体的VHL-/-细胞的肿瘤生长，而在产生2B型突变体的细胞中敲低HIF2α则产生相反的效果。因此，HIF失调方面的定量差异足以解释与VHL突变相关的肾癌的不同风险。
